Familial Mental Handicap *

apparently aged men, seated together around a table and apart from the other patients. They smiled; spoke a few words; gabbled or jargonised. My companion said, "They like to dine together". On complimenting him for his attention to their wishes, he answered, "Oh, they are all brothers". On going to the department for females, I observed two quiet, elderly women, indulged in the same way. "These", said my guide, "are sisters, and sisters of the five brothers. They were the children


s should be c
nsidered in the aetiology of non-specific mental handicap as a whole, but it was Turner and Turner   (1974) who stressed the importance of this.They further concluded that X-linked genes were re- sponsible for the cond tion in 20% of affected males in New South Wales.More recent studies by Herbst * Abbreviated version of the paper presented at the 6th International Congress of the International Association or the Scientific Study of Mental Deficiency, Toronto, Canada (August 1 982).

Figure 1 Reproduction of a photograph in 1862 of seven mentally handicapped brothers and sisters.

Figure 1 Reproduction of a photograph in 1862 of seven mentally handicapped brothers and sisters.

and Miller (1980) in British Columbia gave an incidence of at least 1.83 per 1000 males for Xlinked mental handicap.

The new chapter on X-linked mental handicap began in 1969 when Lubs reported the presence of a marker X-chromosome in affected males belonging to a family whose pedigree indicated X-linked mental handicap.

There was no further progress made until 1977 when Harvey et al reported an identical marker X- chromosome in a portion of metaphases from males of four such families.Sutherland (1977) showed that this marker was in fact a 'fragile site' occurring at band q 27 or q 28 of the X-chromosomes.He pointed out that the culture conditions were critical if the fragile site on the X-chromosome were to be expressed.

The studies mentioned so far, and many others, have been reviewed and reported in the American Journal of Medical Genetics Genetic drift (1980).


STOKE PARK STUDY

Since 1930 when the research centre was established at Stoke Park, detailed records of mental and physical disorde s of the families and their siblings have been kept and constantly updated.However, since patients were admitted between 1909 and 1948 from every county of England and Wales and between 1948 and 1974 from the West of England, a d at present, from a district catchment area of 222,000 population, family histories are often in- complete or not available; therefore, in the present study we are relying only on data available from the records of the patients in the hospital.

Many pa ers on the heredity of familial mental handicap, X-linked conditions, biochemical and chromosomal abnormalities and other disorders were published at Stoke Park (Jancar, 198 ).

The present study is an analysis of randomly collected, 1000 families, whose children were ad- mitted to the Stoke Park Group of Hospitals, with special emphasis on the families with more than one mentally handi apped child.

It was found that members of families were affected as shown in Table 1.The Lyon hypothesis (1962) in part explains the preponderance of males affected by mental handicap (Table 2).

It is interesting to note that by far the commonest combination of affected siblings was in families with one male and one female mentally handicapped member (62%), whereas in total males were only slightly more numerous than females.Congenital Syphilis, in the pre-antibiotic era, af- fected 12 families with more than one mentally There were 1 97 cases of Down's syndrome amongst the 1000 famili s -1 32 males and 65 females.Family history of Down's syndrome was noted in three families with males only affected.

In the families with more than one male, two examples of X-linked conditions are presented:

(1) Nome's disease (Recessive, sex-linked, pro- gressive oculocerebral degeneration) Two brothers with Norrie's isease, who were severely mentally handicapped, epileptic and died at Stoke Park Hospital from pulmonary tuberculosis, had 12 male relatives in five generations, who had all suffered from Norrie's disease (Jancar 1980).

(2) Lesch-Nyhan syndrome (Familial Hyper-


uricemia)

The propositus of the first Bristol family discovered to suffer from this disease died last July at the age of 33.He had two brothers and a nephew afflicted with the same disorder characterised by severe mental handicap, self mut

ation, choreoathetotic move-
ments and history of e

lepsy (Jancar and
Wiley 1973).

An example of the families with more than one handicapped female is familial tapetoretinal de- generation.There are three mentally handicapped sisters and a great niece similarly affected who has in addition cerebellar ataxia, epilepsy and deafness.There are other disorders in this family.The mother and one sister suffered from rheumatoid arthritis; the father and his grandson suffered from diabetes mel- litus; the youngest sibling had a patent intraven- tricular septum; and two nephews are mentally handicapped.One miscarriage and one infant death are noted in the sam generation (Jancar and   Walters 1974).

Two examples of the families with male and female siblings are as follows:

(1) Female, severely mentally handicapped with history of superimpo ed psychotic episodes, retinitis pigmentosa, deafness and generalised dyskinesia, had an older brother who suffered from blindness and a degree of deafness.The patient's younger brother was deaf and dumb and partially sight d (Jancar 1970).

(2) Brother and sister suffering from phenylketonuria, evere mental handicap and epilepsy.Both patients have, in addition, bilateral calcified choroid plexus, and th ir paternal grandfather suffered from epilepsy.


FRAGILE X-LINKED MENTAL HANDICAP

Since 1980 when the new techniques for demon- strating the presence of the fragile X marker chromosome became available we have been reexamining cases with X-linked familial mental handi- cap.So far 18 cases, including one female, have been diagnosed from seven 'families.The clinical characteristics, particularly the facial features and macro-orchidism in association with mental handicap, have enabled the diagnosis to be made in four other singleton cases.The fragile X chromosome has been identified in only a proportion of the mentally handicapped members of these families.
n some of the families there is only one mentally handicapped child; these families also need further study (McDermott and Walters 1982).

Two families in which fragile X-linked mental handicap was confirmed had to be reclassified.In one, the siblings three males and one female had all the signs and symptoms of Rubinstein-Taybi syndrome (Jancar 1965), and in the o her family, where three brothers were originally labelled as Renpenning syndrome (Tredgold 1979).


EXAMPLES OF RARE SYNDROME

The following rare syndromes were noted in the survey of 1000 families: Mandibulo-facial dysostosis (two brothers), Prader-Willi syndrome (two brothers), Sturge-Weber syndrome (male and two men- tally handicapped, epileptic cousins), Marfan syndrome (mother and daughter), Hurler syndrome (two brothers and one cousin), and Right-sided hemiplegia (two brothers).


PSYCHIATRIC ASPECTS

It was frequently noted among 1000 families, par- ticularly in the families with Down's syndrome si - lings, that there was an occurrence of a variety of mental disorders.Thes mental disorders are, at present, the subject of a separate study.The im- portance of a study of psychiatric disorder in relatives of mentally handicapped patients must be em- phasised.Penrose in 1966 stated: The various branches of psychiatry all have potential value for each other.Provided that we do not neglect or despise the data derived from one another's discipline, there are advances to be made in the diagnosis, prevention and treatment of apparently most intractable mental disease.'


CONCLUSION

The studies and urveys, including the Stoke Park Study, of familial mental handicap can be grouped into four areas:

(1) Pre-Penrose Survey (1938)   When pioneers in the field of mental handicap accumulated data proving that heredity plays a major role in causation of mental handicap.

(2) Post-Penrose Survey Penrose reported in his survey a

excess of males among ment
lly handicapped patients.This obser- vation stimulated a number of worke s to study X- linked pedigrees and they came to the conclusion that X-linked genes were responsible for non- specific mental handicap in males.

(3) Post-Lubs Era Since Lubs reported in 1969 the presence of a marker X-chromosome in affected males, in X-linked mental handicap pedigree, new

xciting developments
have taken place particularly with the discovery of Fragile X chromosome by Sutherland.The Fragile X has been found in autistic children and by amniotic tap for prenatal diagnosis.Fragile sites in other chromosomes have been described which may prove to be important in the future studies of mental handicap.

(4) Era of Treatment Lejeune (1982) in a letter to the Lancet stated that fragility of the X-chromosome can be rectified in vitro by thymine, folic acid, 5-formyltetrahydrofolate, or even amino-acids, precursors of 'monocarbons' and he postulated that monocarbon disorder could be a major cause of mental deficiency, and he suggested an interesting possibilit

of treating
the pregnant Fragile X women in view of his experience of treating a Fragile X 1? year old child with folic acid.

Le eune concluded his letter: 'Research on the treatment of Fragile X patients has only just begun but this could be the first example in history of cytogenetics where a hromosome associated disease related to a partly-understood chemical abnormality has proved amenable to treatment.Preliminary find- ings give rise to the hope that cytogenetics will some day become another chapter of true medi- cine that is, curative medicine.'

The message for the future is quit clear.It in- dicates that when no causes are known, cases should be examined and re-investigated.Cytogenetic and other findings may provide a base for genetic counselling, and known or still to be dis- covered treatment.


SUMMARY

One thousand families, randomly collected, whose mentally handicapped children were admitted to Stoke Park Group of Hospitals, were studied.The findings, relating to the number of affected siblings, sex predominance, congenital syphilis, consang inity, fragile X-linked mental handicap, Down's syn- drome and other rare syndromes, were analysed and where appropriate illustrated with a few examples.The psychiatric aspect of familial mental handicap has been emphasised.The relevant literature on the subject of familial mental handicap was reviewed.

Table 1
1Families with only one memberaffected591 = 59.1%(Females 209= 20.9%)(Males 382= 38.2%)Families with more than one76 =7.6%male affectedFamilies with more than one54 =5.4%fem

esearch
ssistant and Psychologist, who has worked for over 40 years at Stoke Park, for invaluable documenta- tion, psychological examinations of the patients and help with researching relevant data; Dr. Graham Carter of Stoke Park Hospital for the help with statistical analysis; Dr. Alan McDermott, Regional Cytogeneticist, Southmead Hospital, Bristol for cytogenetic examination; and Miss Deborah K. Britt for the secretarial work.
Mental defectives-their history, treatment and training. W Barr, 1904Rebman LimitedLondon

Group of seven idiots, brothers and